The objectives of this proposal are to create a multi-scale, finite element (FE) model of the human body that combines dynamic muscle modeling and structural FE analysis into a single framework, to validate the model at multiple scales by comparison to in vitro and in vivo data, and to apply the modeling framework to subject- specific analyses of the natural and TKR implanted knee during activities of daily living. The FE framework allows for interchangeable rigid and deformable representations of the tissues, which enables stress and strain evaluation in muscle, ligament and cartilage structures. Current computational models of the musculoskeletal system do not incorporate into a single framework the multi-scale complexity of the musculoskeletal system, the force and redundancy of the many muscles spanning the joints, and the deformability of the tissues. Due in part to these limitations, computer models and simulations are not widely applied in orthopedics and musculoskeletal research. The specific aims of this proposal will address these limitations and accelerate innovation in human modeling and simulation by opening a new path for more realistic representation of human tissue. For the first time, muscle forces for test subjects will e predicted by optimization within a single multi-scale deformable modeling framework. Significantly, accurate knowledge of the forces, stresses and strains transmitted to the tissues cuts across many scales and disciplines. This ground-breaking initiative will help engineers, clinicians, and researchers to create and improve the design of surgical procedures, rehabilitation protocols, prosthetics and implants, and improve understanding of injury and disease.